Roles of engrailed proteins in granule cells during cerebellum development

描述（由申请人提供）：小脑是位于后脑上方的后脑结构，协调运动和认知功能。在这个建议中，我的目的是确定小脑发育不全的细胞和分子机制，导致删除的enrailed（EN）同源框转录因子EN 1和EN 2（统称为EN 1/2）从颗粒细胞祖细胞（GCPs）在外部生发层（EGL）的发育小脑（Cb）。由于在这些突变体中未检测到主要的细胞结构缺陷，因此必须存在其他细胞类型的细胞非自主稳态缩放以补偿产生的颗粒神经元群体减少。在器官内以适当的数量和位置指定细胞类型代表了生物系统开发中的关键挑战，对于该器官的内在功能以及关于该器官在整个生物体内的操作。在神经系统中，神经元亚型的群体大小的变化可以影响突触后和突触前神经元的规格或存活，这一效应首先由Viktor Hamburger和Rita Levi-Montalcini发现的经典神经营养假说证明。在许多疾病中，如小头畸形，精神分裂症和自闭症谱系障碍，大脑亚区大小的变化的观察，特别强调了神经发育中的大小调节的重要性。本研究主要包括两个目的：1）确定由EN 1/2调控的Cb GCP中的细胞过程以及EN 1/2突变体GCP对主要促分裂原Sonic Hedgehog（SHH）的反应性; 2）鉴定EN 2直接DNA结合序列和由EN 1/2调控的相关基因，它们是发育中Cb中EN 1/2调控GCP行为的下游效应子。

DESCRIPTION (provided by applicant): The cerebellum is a posterior brain structure located above the hindbrain that coordinates motor and cognitive function. In this proposal, I aim to determine the cellular and molecular mechanism responsible for the cerebellar hypoplasia that results from removal of the engrailed (EN) homeobox transcription factors EN1 and EN2 (refered to together as EN1/2) from granule cell progenitors (GCPs) in the external germinal layer (EGL) of the developing cerebellum (Cb). Since major cytoarchitectural defects are not detected in these mutants, there must be cell non-autonomous homeostatic scaling of other cell types to compensate for the reduced granule neuron population generated. Specification of cell types in appropriate number and position within an organ represents a key challenge in development of biological systems, both for the intrinsic function of that organ and with regards to operation of that organ within the whole organism. In neural systems, changes in the population size of neuron subtypes can affect specification or survival of post- and presynaptic neurons, an effect first demonstrated by the now classic neurotrophic hypothesis discovered by Viktor Hamburger and Rita Levi-Montalcini. The importance of size regulation in neural development is particularly emphasized by the observation of changes in brain subregion size in numerous diseases, such as microcephaly, schizophrenia and autism spectrum disorder. The proposed study involves two major aims: 1) determine the cellular processes regulated by EN1/2 in GCPs of the Cb and the responsiveness of EN1/2 mutant GCPs to the major mitogen Sonic Hedgehog (SHH); and 2) identify EN2 direct DNA binding sequences and associated genes regulated by EN1/2 that are downstream effectors of EN1/2 regulated GCP behaviors in the developing Cb.